Due to a lack of direct funding for the project (only administrative costs related to the PI's position were provided by the institute) the study had to focus on developing novel ideas, which would allow to test the safety of the new p5 peptide in various animal species using our lentiviral vector-encoded p5 transgene. Through meta-analysis of published literature, we have theoretically developed relatively easy and accurate approaches to answer questions about peptide toxicity in general and in particular during neural development and cognition. In the unlikely event that the peptide is toxic when delivered systemically, post-developmental local transgene expression would still be possible and could bypass toxicity. The transgene delivery vehicle and route will ultimately depend on the neurodegenerative disease, the location of the affected target cells including their connectome (i.e. spinal cord, cortex, brain stem, peripheral nerves). Therapeutic efficacy will be measured by the reduction in Cdk5/p25 hyperactivity and by an amelioration of disease progression or prevention. Taken into account recent publications describing efficient neuronal transport by AAV9 vectors and the use of lentiviral vector-transduced autologous hematopoietic stem cells for transplantation and gene delivery to the CNS, we can adapt and scale up different p5-transgene delivery strategies as needed for different neurodegenerative diseases in larger animal species. The experience gained from the transgene delivery will also benefit the field of gene therapy in general, independent of the transgene. For these ideas to materialize and to test the newly synthesized p5-transgene in vivo, direct costs for the project would have to be provided. In addition, the study will benefit from multidisciplinary collaborations with PIs who are experts for individual disease entities or for diverse technologies that will be required. The study could become an inter-institutional effort at the NIH campus, with animal models housed by various institutes.